trial of nelarabine, etoposide and cyclophosphamide in relapsed t-cell all and t-cell ll

Conditions: Relapsed T-Cell Acute Lymphoblastic Leukemia; Relapsed T-Cell Lymphoblastic Lymphoma

Summary: nelarabine has shown significant activity in patients with t-cell malignancies. this study will determine the safety and maximum tolerated dose of the combination of nelarabine, cyclophosphamide and etoposide in patients with first bone marrow relapse of t-all, or first relapse of t-ll.


Eligibility criteria:
inclusion criteria: * patients to be enrolled in the dose-escalation portion of this study must have t-cell all or t-cell lymphoblastic lymphoma (ll) in first relapse or must have failed primary induction chemotherapy (ie, never attained a complete remission following an initial course of standard therapy for t-all or t-ll). patients to be enrolled in the cohort expansion portion of this study (ie, those treated at the recommended phase 2 dose) must have t-cell all in first relapse or must have failed primary induction chemotherapy (ie, never attained a complete remission following an initial course of standard therapy for t-all). t-ll patients are not eligible for the cohort expansion phase. * patients with t-cell all must have greater than 25% blasts in the bone marrow with or without extramedullary disease. * patients with t-cell ll must have recurrent disease, documented by clinical or radiographic criteria, as well as histologic verification of the malignancy at original diagnosis. patients with t-cell ll enrolled in the phase i dose-escalation study are not required to have measurable disease; however, patients enrolled in the phase ii cohort expansion at the mtd must have measurable disease. * patients may have cns 1 or cns 2 disease but not cns 3. * ecog 0-2 or karnofsky ≥ 50% for patients \> 16 years of age; lansky ≥ 50% for patients ≤16 years of age. * patients may be enrolled on study regardless of the timing of prior intrathecal therapy; however, they may not begin treatment on this protocol until a minimum of 7 days has elapsed since prior intrathecal therapy. * at least 6 weeks must have elapsed since administration of nitrosureas. * at least 12 weeks must have elapsed since administration of craniospinal or hemipelvic radiation. * female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment. * female patients with infants must agree not to breastfeed their infants while on this study. * male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for a minimum of 6 months after study treatment. * adequate renal function defined as serum creatinine ≤ 1.5x upper limit of normal (uln) for age. if the serum creatinine is above these values, the calculated creatinine clearance or radioisotope gfr must be ≥ 70 ml/min/1.73m2. * total bilirubin ≤ 1.5x uln for age. if the total bilirubin is elevated, patient will still be eligible if the conjugated (direct) serum bilirubin ≤ uln for age. * alt ≤ 5x uln of normal for age. * adequate cardiac function defined as shortening fraction of ≥ 27% by echocardiogram or ejection fraction ≥ 45% by gated radionuclide study. * no evidence of dyspnea at rest * no exercise intolerance * a pulse oximetry ≥ 94% at sea level (≥ 90% at altitude ≥ 5000 feet) if there is clinical indication for determination. * patients and/or their parents or legal guardians must be capable of understanding the investigational nature, potential risks and benefits of the study. all patients and/or their parents or legal guardians must sign a written informed consent. exclusion criteria: * patients with down syndrome are excluded. * patients with pre-existing grade 2 (or greater) peripheral motor or sensory neurotoxicity per the ctcae 3.0 as determined by the treating physician or a neurologist. * patients with a history of prior veno-occlusive disease (vod) or findings consistent with a diagnosis of vod, defined as: conjugated serum bilirubin \>1.4 mg/dl and unexplained weight gain greater than 10% of baseline weight or ascites and hepatomegaly or right upper quadrant pain without another explanation, or reversal of portal vein flow on ultrasound, or pathological confirmation of vod on liver biopsy. * previous hematopoetic stem cell transplantation. * patients with a prior seizure disorder requiring anti-convulsant therapy are not eligible to receive nelarabine. for the purposes of this study, this includes any patient that has received anticonvulsant therapy to prevent/treat seizures in the prior two years. * positive blood culture within 48 hours of study enrollment. * fever above 38.2 within 48 hours of study enrollment with clinical signs of infection. * plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period. * any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.

Keywords: relapse t cell lymphoblastic leukemia lymphoma nelarabine tacl nectar